Much work over the past decade has implicated hyperactivity in the auditory system as an important neural correlate of tinnitus. For some forms of tinnitus, this hyperactivity is first observed in the dorsal cochlear nucleus (DCN), where it is triggered by loss of normal input from the auditory nerve. The ability to develop effective treatments for tinnitus is likely to be enhanced by a better understanding of a) the cellular origins and underlying mechanisms of tinnitus-related hyperactivity in the DCN b) how this activity is controlled by descending inputs from higher order auditory centers, and c) how DCN hyperactivity influences the emergence of hyperactivity at higher levels of the auditory system. The proposed research will take major steps toward the fulfillment of all three needs. Aims 1 and 2 will apply a combination of electrophysiological and pharmacological approaches to determine the relative importance of receptor-mediated plasticity and ion channel alterations as underlying mechanisms of hyperactivity. Aim 3 will investigate the influence of descending pathways from other brainstem auditory nuclei on the level of hyperactivity in the DCN. We will focus on two different centrifugal pathways, one from the inferior colliculus and the other from the superior olivary complex. The influence of these pathways on DCN hyperactivity will be investigated by selective lesioning, as well as by electrical and acoustic stimulation of their structures of origin. Aim 4 will examine the long-term consequences of noise exposure on the chemistry of auditory centers at brainstem levels of the auditory system. Aim 5 will focus on the inferior colliculus as a possible generator site of tinnitus related hyperactivity. We will use electrophysiological recording methods to demonstrate that hyperactivity develops in the inferior colliculus as a result of intense noise exposure. The DCN will then be ablated to determine whether IC hyperactivity persists or disappears. The results will enable us to establish whether the IC is an independent site of tinnitus generation or instead, simply receives this hyperactivity from the DCN level. The deeper understanding of tinnitus mechanisms to be obtained from this study will provide a basis for translational research oriented toward the development of anti-tinnitus therapies. Relevance: The ability to develop effective treatments for tinnitus is likely to be enhanced by a) a better understanding of the cellular origins and underlying mechanisms of tinnitus- related hyperactivity in the dorsal cochlear nucleus, and b) how this activity might be controlled by descending inputs from higher order auditory centers. The proposed research will take major steps toward the fulfillment of both needs. The deeper understanding of tinnitus mechanisms to be obtained from this study will provide a basis for translational research oriented toward the development of anti-tinnitus therapies.